Amino-and amido-diphenyl ethers

ABSTRACT

The invention relates to novel amino- and amido-diphenyl ethers, processes for their preparation and their use in pharmaceuticals, in particular for the indications of arteriosclerosis and hypercholesterolaemia.

[0001] The invention relates to novel amino- and amido-diphenyl ethers,processes for their preparation and their use in pharmaceuticals, inparticular for the indications of arteriosclerosis andhypercholesterolaemia.

[0002] European Application 580 550 A (Ciba Geigy; 1994) describesoxamic acid derivatives having cholesterol-lowering properties inmammals. This application describes an in vitro test based on thebinding to thyroid hormone cell receptors (so-called T₃ nuclearreceptors). The pharmacological property which is stressed is thereduction in plasma cholesterol, in particular LDL cholesterol.Cholesterol-lowering effects are also described in the EuropeanApplication EP-A-188 351 (SKF; 1986) for certain diphenyl ethers withthyroid hormone-like effects.

[0003] It has now been found that the compounds of the general formula(I)

[0004] in which

[0005] R¹⁰ represents nitro, amino, acetamido or represents a group ofthe formula —NH—CO—CO—A or —NH—CH₂—CO—A, in which

[0006] A represents hydroxyl or (C₁-C₄)-alkoxy,

[0007] R² and R³ are identical or different and denote halogen,C₁-C₄-alkyl or trifluoromethyl,

[0008] R⁴ represents a group of the formula

[0009]  in which

[0010] E represents straight-chain or branched (C₁-C₄)-alkyl,

[0011] R⁶ and R⁷ are identical or different and, independently of oneanother, represent straight-chain or branched (C₁-C₁₀)-alkyl which canbe substituted one or more times, identically or differently, by(C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, amino, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₄)-alkoxycarbonylamino, aminocarbonyl,(C₁-C₆)-alkoxycarbonyl, or by (C₆-C₁₀)-aryl or 5 to 6-membered saturatedor aromatic heterocyclyl with up to three heteroatoms from the series N,O and/or S, where aryl and heterocyclyl in turn are optionallysubstituted one or more times, identically or differently, by(C₁-C₄)-alkyl, aminocarbonyl, (C₁-C₄)-alkanoylamino or halogen,

[0012]  represent (C₆-C₁₀)-aryl or (C₃-C₈)-cycloalkyl, each of which canbe substituted by (C₁-C₄)-alkoxy, or

[0013]  represent a 4- to 8-membered saturated heterocycle with up totwo heteroatoms from the series N, O and/or S, which can be substitutedone or more times, identically or differently, by(C₁-C₄)-alkoxycarbonyl, oxo or (C₁-C₄)-alkyl, or

[0014] R⁶ and R⁷ form, together with the nitrogen atom to which they arebonded, a 4- to 7-membered saturated heterocycle which optionallycontains up to two other heteroatoms from the series N, O and/or S,

[0015] R⁸ represents straight-chain or branched (C₁-C₁₀)-alkyl which canbe substituted by (C₃-C₈)-cycloalkyl, phenyl or phenoxy, or represents(C₃-C₈)-cycloalkyl, (C₆-C₁₀)-aryl, biphenylyl or (C₁-C₆)-alkoxy,

[0016] R⁹ represents straight-chain or branched (C₁-C₈)-alkyl whosecarbon chain can be interrupted by —O— and which can be substituted by(C₃-C₈)-cycloalkyl or phenyl, or represents (C₃-C₈)-cycloalkyl,(C₂-C₆)-alkenyl, phenyl or pyridyl,

[0017]  where the aromatic ring systems mentioned both in R⁸ and in R⁹can, in each case independently of one another, in turn be substitutedby trifluoromethyl, halogen, (C₁-C₄)-alkoxy, (C₁-C₄)-alkyl or amino, or

[0018] R⁸ and R⁹ form, together with the nitrogen atom and the carbonylgroup to which they are bonded, a 4- to 7-membered saturated heterocyclewhich optionally contains up to two other heteroatoms from the series N,O and/or S,

[0019] R¹⁰ represents straight-chain or branched (C₁-C₁₅)-alkyl whichcan be substituted by (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy, phenyl,phenoxy or benzyloxy, where the said aromatic radicals can in turn eachbe substituted up to three times, identically or differently, byhalogen, (C₁-C₆)-alkyl or (C₁-C₄)-alkoxy,

[0020]  represents (C₃-C₈)-cycloalkyl which can be substituted by(C₁-C₄)-alkoxy or phenyl,

[0021]  represents (C₆-C₁₀)-aryl which can be substituted up to threetimes, identically or differently, by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halogen, cyano, amino, trifluoromethyl or phenyl, or

[0022]  represents a 5- to 6-membered saturated or aromatic, optionallybenzo-fused heterocycle with up to two heteroatoms from the series N, Oand/or S, or

[0023]  denotes a group of the formula —OR¹³ or NR¹⁴R¹⁵, in which

[0024] R¹³ represents straight-chain or branched (C₁-C₆)-alkyl, and

[0025] R¹⁴ and R¹⁵ are identical or different and, independently of oneanother,

[0026]  represent hydrogen, straight-chain or branched (C₁-C₁₂)-alkyl,which can be substituted by aminocarbonyl, a group of the formula—NR¹⁶R¹⁷, 5- to 6-membered heteroaryl which contains up to 3 heteroatomsselected from the series N, O and/or S or can be substituted by phenyl,where phenyl is optionally substituted up to twice, identically ordifferently, by halogen, (C₁-C₄)-alkyl, trifluoromethyl or(C₁-C₄)-alkoxy,

[0027]  represent (C₃-C₈)-cycloalkyl which can be substituted by(C₁-C₄)-alkyl, represent (C₆-C₁₀)-aryl which can be substituted up tothree times, identically or differently, by halogen, (C₁-C₄)-alkyl,trifluoromethyl, (C₁-C₄)-alkoxy, amino, phenyl or phenoxy, or

[0028]  represent a 5- to 7-membered, saturated or unsaturatedheterocycle which contains one or two nitrogen atoms and which can bebonded via a carbon or nitrogen atom and is optionally substituted by(C₁-C₄)-alkyl or an oxo group, where

[0029] R¹⁶ and R¹⁷ are identical or different and, independently of oneanother, represent hydrogen, (C₁-C₆)-alkyl, phenyl or(C₆-C₁₀)-arylsulphonyl, or

[0030]  form, together with the nitrogen atom to which they are bonded,a 3- to 7-membered saturated heterocycle which optionally contains up totwo other heteroatoms from the series N, O and/or S, or

[0031] R¹⁴ and R¹⁵ form, together with the nitrogen atom to which theyare bonded, a 4- to 7-membered saturated heterocycle which can containup to two other heteroatoms from the series N, O and/or S and besubstituted by amino, (C₁-C₆)-alkyl, (C₁-C₄)-alkanoyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkoxycarbonylamino, phenyl or pyridyl,

[0032] R¹¹ and R¹² are identical or different and, independently of oneanother,

[0033]  represent hydrogen, straight-chain or branched (C₁-C₆)-alkyl,which can be substituted one or more times, identically or differently,by mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, (C₁-C₄)-alkoxy,(C₁-C₆)-alkoxycarbonyl, carboxyl, pyridyl or (C₆-C₁₀)-aryl, where thelatter in turn is optionally substituted by halogen, trifluoromethyl,(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy,

[0034]  represent (C₃-C₈)-cycloalkyl or represent a 5- to 7-memberedheterocycle which contains one to two nitrogen atoms and which can bebonded via a carbon or nitrogen atom, where cycloalkyl and heterocycleare optionally substituted by (C₁-C₄)-alkyl, or

[0035] R¹¹ and R¹² form, together with the nitrogen atom to which theyare bonded, a 5- to 7-membered saturated, optionally benzo-fusedheterocycle which can contain up to two other heteroatoms from theseries N, O and/or S and be substituted by amino, (C₁-C₆)-alkyl,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkoxycarbonylamino or phenyl, and

[0036] R⁵ denotes hydrogen, (C₁-C₄)-alkyl or (C₁-C₄)-alkanoyl,

[0037] and the respective salts and hydrates thereof show apharmacological effect and can be used as pharmaceuticals or forproducing pharmaceutical formulations.

[0038] Heteroaryl is intended to mean for the purposes of the inventionin general a 5- to 8-membered aromatic, optionally benzo-fusedheterocycle with up to 4 heteroatoms from the series S, N and/or O.Examples which may be mentioned are: pyridyl, thienyl, thiazolyl,oxazolyl, imidazolyl, triazolyl, tetrazolyl.

[0039] Heterocycles are intended to mean for the purposes of theinvention generally a 5- to 8-membered, saturated, partially unsaturatedor aromatic, optionally benzo-fused heterocycle with up to 4 heteroatomsfrom the series S, N and/or O, that is to say a heterocycle which maycontain one or more double bonds and which is linked via a ring carbonatom or a ring nitrogen atom. Examples which may be mentioned are:tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl,piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl,piperazin-1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl,furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl,pyrimidyl, pyrazinyl, pyrimidinonyl, pyridazinonyl.

[0040] Those in this list which are preferred are: pyrimidyl,pyridazinyl, pyrimidinonyl, pyridazinonyl.

[0041] (C₁-C₁₅)-Alkyl, (C₁-C₁₂)-alkyl, (C₁-C₁₀)-alkyl, (C₁-C₈)-alkyl,(C₁-C₆)-alkyl, (C₁-C₄)-alkyl and (C₁-C₃)-alkyl represent for thepurposes of the invention a straight-chain or branched alkyl radicalrespectively with 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 and1 to 3 carbon atoms. A straight-chain or branched alkyl radical with 1to 3 carbon atoms is preferred. Preferred examples which may bementioned are: methyl, ethyl, n-propyl, isopropyl, n-, i-, s- ort-butyl, n-pentyl and n-hexyl.

[0042] (C₆-C₁₀)-Aryl represents for the purposes of the invention anaromatic radical with 6 to 10 carbon atoms. Preferred aryl radicals arephenyl and naphthyl.

[0043] (C₃-C₈)-Cycloalkyl, (C₃-C₇)-cycloalkyl and (C₃-C₆)-cycloalkylrepresent for the purposes of the invention a cycloalkyl grouprespectively with 3 to 8, 3 to 7 and 3 to 6 carbon atoms. Those whichmay be mentioned as preferred are: cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

[0044] (C₂-C₆-Alkenyl represents for the purposes of the inventionstraight-chain or branched alkenyl with 1 to 3 double bonds and 2 to 6carbon atoms, preferably 1 or 2 double bonds and 2 to 4 carbon atoms,particularly preferably 1 double bond and 2 or 3 carbon atoms. Examplesare: vinyl, allyl, prop-1-en-1-yl, isopropenyl, but-1-enyls,but-2-enyls, buta-1,2-dienyls, buta-1,3-dienyls.

[0045] (C₁-C₆)-Monoalkylamino represents a straight-chain or branchedalkylamino radical with 1 to 6 carbon atoms. A straight-chain orbranched alkylamino radical with 1 to 4 carbon atoms is preferred.Examples which may be mentioned are: methylamino, ethylamino,n-propylamino, isopropylamino, tert-butylamino, n-pentylamino andn-hexylamino. A straight-chain or branched alkylamino radical with 1 to3 carbon atoms is particularly preferred.

[0046] (C₁-C₆)-Dialkylamino represents a straight-chain or brancheddialkylamino radical where the alkyl radicals can be identical ordifferent and each contains 1 to 6 carbon atoms. A straight-chain orbranched dialkylamino radical where each alkyl radical contains 1 to 4carbon atoms is preferred. Examples which may be mentioned are:dimethylamino, diethylamino, di-n-propylamino, diisopropylamino,di-t-butylamino, di-n-pentylamino, di-n-hexylamino, ethylmethylamino,isopropylmethylamino, n-butylethylamino, n-hexyl-1-pentylamino. Astraight-chain or branched dialkylamino radical with 1 to 3 carbon atomsis particularly preferred.

[0047] (C₁-C₆)-Alkoxycarbonylamino represents a straight-chain orbranched alkoxycarbonylamino radical with 1 to 6 carbon atoms. Astraight-chain or branched alkoxycarbonylamino radical with 1 to 4carbon atoms is preferred. Examples which may be mentioned are:methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,isopropoxycarbonylamino, tert-butoxycarbonylamino,n-pentoxycarbonylamino and n-hexoxycarbonylamino. A straight-chain orbranched alkoxycarbonylamino radical with 1 to 3 carbon atoms isparticularly preferred.

[0048] (C₁-C₆)-Alkoxycarbonyl represents a straight-chain or branchedalkoxycarbonyl radical with 1 to 6 carbon atoms. A straight-chain orbranched alkoxycarbonyl radical with 1 to 4 carbon atoms is preferred.Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Astraight-chain or branched alkoxycarbonyl radical with 1 to 3 carbonatoms is particularly preferred.

[0049] (C₁-C₆)-Alkoxy represents for the purposes of the invention astraight-chain or branched alkoxy radical with 1 to 6 carbon atoms. Astraight-chain or branched alkoxy radical with 1 to 3 carbon atoms ispreferred. Examples which may be mentioned are: methoxy, ethoxy,n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

[0050] (C₁-C₄)-Alkanoyl represents for the purposes of the invention astraight-chain or branched alkyl radical with 1 to 4 carbon atoms whichhas a doubly bonded oxygen atom in the 1 position and is linked via the1 position. Examples which may be mentioned are: formyl, acetyl,propionyl, n-butyryl, i-butyryl.

[0051] (C₁-C₄)-Alkanoylamino represents for the purposes of theinvention a radical of the formula

Alk-CO—NH—

[0052] in which the group Alk-CO— represents a (C₁-C₄)-alkanoyl radicalas defined above.

[0053] Amino represents for the purposes of the invention the NH₂ group.

[0054] Aminocarbonyl represents for the purposes of the invention theH₂NCO— group.

[0055] (C₁-C₄)-Alkoxycarbonylamino represents for the purposes of theinvention a radical of the formula

AlkO-CO—NH—

[0056] in which the group AlkO-CO— represents a (C₁-C₄)-alkoxycarbonylradical as defined above.

[0057] Halogen includes for the purposes of the invention fluorine,chlorine, bromine, and iodine. Fluorine, chlorine or bromine ispreferred.

[0058] The compounds according to the invention may, depending on thesubstitution pattern, exist in stereoisomeric forms which either arerelated as image and mirror image (enantiomers) or are not related asimage and mirror image (diastereomers). The invention relates both tothe enantiomers or diastereomers and to respective mixtures thereof. Theracemic forms can, just like the diastereomers, be separated into thestereoisomerically pure constituents in a known manner.

[0059] Certain compounds may furthermore exist in tautomeric forms. Thisis known to the skilled person, and such compounds are likewiseencompassed by the scope of the invention.

[0060] The compounds according to the invention may also be in the formof salts. Physiologically acceptable salts are preferred for thepurposes of the invention.

[0061] Physiologically acceptable salts may be salts of the compounds ofthe invention with inorganic or organic acids. Preference is given tosalts with inorganic acids, such as, for example, hydrochloric acid,bromic acid, phosphoric acid or sulphuric acid, or salts with organiccarboxylic or sulphonic acids such as, for example, acetic acid,propionic acid, maleic acid, fumaric acid, malic acid, citric acid,tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid,ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

[0062] Physiologically acceptable salts may likewise be salts of thecompounds according to the invention with bases, such as, for example,metal or ammonium salts. Preferred examples are alkali metal salts (forexample sodium or potassium salts), alkaline earth metal salts(magnesium or calcium salts), and ammonium salts which are derived fromammonia or organic amines such as, for example, ethylamine, di- ortriethylamine, ethyldiisopropylamine, ethanolamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine,N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine,arginine, lysine, ethylenediamine or 2-phenylethylamine.

[0063] The compounds according to the invention may also be in the formof their solvates, in particular in the form of their hydrates.

[0064] Preference is given to compounds of the general formula (I) inwhich

[0065] R¹ represents acetamido or represents a group of the formula—NH—CO—CO—A or —NH—CH₂—CO—A, in which

[0066] A represents hydroxyl or (C₁-C₄)-alkoxy,

[0067] R² and R³ are identical or different and denote halogen, methylor trifluoromethyl,

[0068] R⁴ represents a group of the formula

[0069]  in which

[0070] E represents straight-chain or branched (C₁-C₄)-alkyl,

[0071] R⁶ and R⁷ are identical or different and, independently of oneanother,

[0072]  represent straight-chain or branched (C₁-C₁₀)-alkyl which can besubstituted one or more times, identically or differently, by(C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy, 5- to 6-membered saturated oraromatic heterocyclyl with up to three heteroatoms from the series N, Oand/or S, or by (C₆-C₁₀)-aryl which in turn is optionally substitutedone or more times, identically or differently, by aminocarbonyl,(C₁-C₄)-alkanoylamino or halogen,

[0073]  represent (C₃-C₈)-cycloalkyl which can be substituted by(C₁-C₄)-alkoxy, or

[0074]  represent a 4- to 8-membered saturated heterocycle with up totwo heteroatoms from the series N, O and/or S which can be substitutedone or more times, identically or differently, by (C₁-C₄)-alkyl,

[0075] R⁸ represents straight-chain or branched (C₁-C₈)-alkyl,(C₃-C₈)-cycloalkyl, (C₃-C₆)-cycloalkylmethyl or phenyl,

[0076] R⁹ represents straight-chain or branched (C₁-C₈)-alkyl whosecarbon chain can be interrupted by —O— and which can be substituted byphenyl, or (C₃-C₈)-cycloalkyl or phenyl which can be substituted byhalogen, trifluoromethyl or (C₁-C₄)-alkyl,

[0077] R¹⁰ represents straight-chain or branched (C₁-C₁₀)-alkyl whichcan be substituted by (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy, phenyl orphenoxy, where the said aromatic radicals can in turn each besubstituted up to three times, identically or differently, by halogen,(C₁-C₃)-alkyl or (C₁-C₄)-alkoxy,

[0078]  represents (C₃-C₈)-cycloalkyl or represents phenyl which can besubstituted up to three times, identically or differently, by(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, halogen or phenyl, or

[0079]  represents a 5- to 6-membered saturated or aromatic, optionallybenzo-fused heterocycle with up to two heteroatoms from the series N, Oand/or S, or

[0080]  denotes a group of the formula —OR¹³ or —NR¹⁴R¹⁵, in which

[0081] R¹³ represents straight-chain or branched (C₁-C₆)-alkyl, and

[0082] R⁴and R⁵ are identical or different and, independently of oneanother,

[0083]  represent hydrogen or straight-chain or branched (C₁-C₆)-alkylwhich can be substituted by phenyl which in turn is optionallysubstituted up to twice, identically or differently, by halogen,(C₁-C₄)-alkyl, trifluoromethyl or (C₁-C₄)-alkoxy,

[0084]  represent (C₃-C₈)-cycloalkyl which can be substituted by(C₁-C₄)-alkyl, or

[0085]  represent phenyl, naphthyl or biphenylyl,

[0086] R¹¹ and, R¹² are identical or different and, independently of oneanother,

[0087]  represent hydrogen or straight-chain or branched (C₁-C₆)-alkylwhich can be substituted by phenyl which in turn is optionallysubstituted by halogen, trifluoromethyl, (C₁-C₄)-alkyl or(C₁-C₄)-alkoxy, or

[0088]  represent (C₃-C₈)-cycloalkyl which can be substituted by(C₁-C₄)-alkyl, and

[0089] R⁵ denotes hydrogen or (C₁-C₄)-alkanoyl,

[0090] and the respective salts and hydrates thereof.

[0091] Particular preference is given to compounds according to theinvention of the general formula (I) in which

[0092] R¹ represents a group of the formula —NH—CO—COOH or —NH—CH₂—COOH,

[0093] R² and R³ are identical or different and denote chlorine,bromine, methyl or trifluoromethyl,

[0094] R⁴ represents a group of the formula

[0095]  in which

[0096] R⁶ and R⁷ are identical or different and, independently of oneanother, represent a straight-chain or branched (C₁-C₈)-alkyl which canbe substituted by (C₅-C₈)-cycloalkyl, pyridyl, furyl, tetrahydrofuryl orone to three times by methoxy or ethoxy, or which is substituted byphenyl which in turn is optionally substituted once to twice,identically or differently, by fluorine, chlorine, aminocarbonyl oracetamido,

[0097]  represent (C₃-C₈)-cycloalkyl which can be substituted by methoxyor ethoxy, or

[0098]  represent pyrrolidinyl or piperidinyl, each of which can besubstituted one or more times by methyl,

[0099] R⁸ represents straight-chain (C₁-C₇)-alkyl,(C₃-C₆)-cycloalkylmethyl, (C₃-C₆)-cycloalkyl or phenyl,

[0100] R⁹ denotes straight-chain or branched (C₁-C₄)-alkyl which can besubstituted by phenyl, or (C₃-C₆)-cycloalkyl or phenyl which can besubstituted by chlorine or fluorine,

[0101] R¹⁰ represents straight-chain or branched (C₁-C₄)-alkyl which canbe substituted by (C₃-C₆)-cycloalkyl, phenyl or phenoxy, where the saidaromatic radicals can in turn each be substituted up to three times,identically or differently, by fluorine, chlorine or (C₁-C₃)-alkyl, or

[0102]  represents biphenylyl, 2,3-dihydro-1-benzofuranyl,3,4-dihydro-2H-1-benzopyranyl or 3,4-dihydro-1H-2-benzopyranyl, or

[0103]  represents a group of the formula —NR¹⁴R¹⁵, in which

[0104] R¹⁴ denotes hydrogen or straight-chain or branched (C₁-C₃)-alkyl,and

[0105] R¹⁵ represents straight-chain or branched (C₁-C₄)-alkyl which canbe substituted by phenyl which in turn is optionally substituted bymethyl, methoxy, trifluoromethyl, fluorine or chlorine, or

[0106]  represents naphthyl, biphenylyl or (C₃-C₆)-cycloalkyl,

[0107] R¹¹ denotes hydrogen or straight-chain or branched (C₁-C₃)-alkyl,and

[0108] R¹² represents straight-chain or branched (C₁-C₄)-alkyl which canbe substituted by phenyl which in turn is optionally substituted bymethyl, methoxy, trifluoromethyl, fluorine or chlorine, or

[0109]  represents cyclopentyl or cyclohexyl, each of which can besubstituted by (C₁-C₃)-alkyl, and

[0110] R⁵ denotes (C₁-C₄)-alkyl or, in particular, hydrogen,

[0111] and the respective salts and hydrates thereof.

[0112] Very particular preference is given to compounds according to theinvention of the general formula (I) in which

[0113] R¹ represents a group of the formula —NH—CO—COOH or—NH—CH₂-—COOH,

[0114] R² and R³ are identical or different and denote chlorine,bromine, methyl or trifluoromethyl,

[0115] R⁴ represents a group of the formula

[0116]  in which

[0117] R⁶ and R⁷ are identical or different and, independently of oneanother,

[0118]  represent straight-chain or branched (C₁-C₈)-alkyl which can besubstituted by phenyl which in turn is optionally substituted once totwice, identically or differently, by fluorine, chlorine, aminocarbonylor acetamido, or can be substituted by (C₅-C₈)-cycloalkyl, pyridyl,furyl, tetrahydrofuryl or once to three times by methoxy or ethoxy,

[0119]  represent (C₅-C₈)-cycloalkyl which can be substituted by methoxyor ethoxy, or

[0120]  represent pyrrolidinyl or piperidinyl, each of which can besubstituted one or more times by methyl, and

[0121] R¹⁰ represents straight-chain or branched (C₁-C₄)-alkyl which canbe substituted by (C₃-C₆)-cycloalkyl, phenyl or phenoxy, where the saidaromatic radicals can in turn each be substituted up to three times,identically or differently, by fluorine, chlorine or (C₁-C₃)-alkyl, or

[0122]  represents biphenylyl, 2,3-dihydro-1-benzofuranyl,3,4-dihydro-2H-1-benzopyranyl or 3,4-dihydro-1H-2-benzopyranyl, and

[0123] R⁵ denotes hydrogen,

[0124] and the respective salts and hydrates thereof.

[0125] Particularly preferred compounds of the general formula (I) arethose in which E represents methylene.

[0126] Particularly preferred compounds are likewise those in which R⁵represents hydrogen.

[0127] The radical definitions listed above in general or indicated inpreferred ranges apply both to the final products of the formula (I) andcorrespondingly to the starting materials and intermediates required forthe preparation in each case.

[0128] The radical definitions specifically indicated in the respectivecombinations or preferred combinations of radicals are also replaced byradical definitions of other combinations as desired, irrespective ofthe combinations of radicals indicated in each case.

[0129] A process for preparing the compounds according to the inventionof the general formula (I) has additionally been found and ischaracterized in that

[0130] (A) compounds of the formula (II)

[0131] in which

[0132] PG² denotes a hydroxyl protective group or a resin suitable forsolid-phase synthesis, and

[0133] R⁴ has the meaning indicated above,

[0134] are reacted in the presence of a base with compounds of thegeneral formula (III)

[0135] in which

[0136] R² and R³ have the meaning indicated above, and

[0137] R^(1′) represents a suitable group from the scope of meanings ofR¹, preferably represents the NO₂ group, and

[0138] Hal represents chlorine or fluorine,

[0139] to give compounds of the formula (IV)

[0140] in which

[0141] R^(1′), R², R³, R⁴ and PG² have the meaning indicated above, or

[0142] (B) compounds of the formula (V)

[0143] in which

[0144] PG² has the meaning indicated above, and

[0145] R represents a suitable precursor of the R⁴ group, preferablyrepresents CHO, (C₁-C₆)-alkoxycarbonyl or nitro,

[0146] are reacted in the presence of a base with a compound of theformula (III)

[0147] in which

[0148] R^(1′), R², Hal and R³ have the meaning indicated above, to givea compound of the formula (VI)

[0149] in which

[0150] R, R^(1′), R², R³ and PG² have the meaning given above,

[0151] and the latter is converted into compounds of the formula (IV) byconverting the substituent R in a suitable manner to the substituent R⁴,

[0152] and in that finally the protective group pG² is eliminated fromthe compound of the formula (IV) and, where appropriate, thesubstituents are modified or derivatized in a suitable way by standardreactions.

[0153] The coupling reactions on compounds of the formulae (II) and(III) or (V) and (III) are normally carried out in a solvent which isinert under the reaction conditions. Examples which may be mentioned aredimethylformamide, dimethylacetamide, N-methylpyrrolidinone,acetonitrile and, in particular, dimethyl sulphoxide.

[0154] Suitable bases are sodium carbonate, potassium carbonate,triethylamine, ethyldiisopropylamine, sodium bicarbonate and, inparticular, Cs₂CO₃. The reaction is normally carried out at atemperature of from 0 to 100° C., preferably 20 to 60° C.

[0155] Hydroxyl protective groups and suitable conditions for theirintroduction and elimination are described in detail in T. W. Greene, P.G. M. Wuts, “Protective Groups in Organic Synthesis, John Wiley andSons, New York, 2nd edition, 1991. Examples of hydroxyl protectivegroups which may be mentioned are:

[0156] trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl,benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl,tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl,4-methoxybenzyloxycarbonyl, tetrahydropyranyl, formyl, acetyl,trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, methoxycarbonylmethyl,[2-(trimethylsilyl)ethoxy]methyl, benzoyl, 4-methylbenzoyl,4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl.

[0157] Compounds of the formula (II) can be prepared by the free OHgroup in compounds of the formula (VII) being protected with aprotective group PG² or attached to a -resin suitable for solid-phasesynthesis, and in the group R being converted by standard reactions intothe group R⁴,

[0158] in which

[0159] R has the meaning indicated above, and

[0160] PG¹ represents a hydroxyl protective group, in particularbenzoyl.

[0161] The compounds of the formula (V) are obtained analogously fromcompounds of the formula (VII) by introducing the group PG² and theneliminating the group PG¹ selectively.

[0162] The process with its two variants is explained by way of exampleby the following diagram:

[0163] The overall process can also be carried out as solid-phasesynthesis. In this case, the compound of the formula (VII) is attachedvia its free OH group to a suitable resin, in which case PG² in theprevious description of the synthesis represents the appropriate resin.The subsequent reactions are carried out on the solid phase, and theresulting compound is finally eliminated from the resin. Where it isintended to prepare compounds of the general formula (I) in which R⁵does not represent hydrogen, it is possible to modify the resultingcompound further.

[0164] Solid-phase synthesis and the attachment of and elimination fromthe resin are familiar standard techniques. As an example of thecomprehensive literature, reference may be made to the article “Linkersfor Solid Phase Organic Synthesis, Ian W. James, Tetrahedron 55 (1999),4855-4946”.

[0165] The compounds according to the invention of the formula (I) showa surprising and valuable range of pharmacological actions and cantherefore be employed as versatile medicaments. In particular, they canbe employed for all indications which can be treated with naturalthyroid hormones, such as, for example and preferably, depression,goitre or thyroid cancer. It is possible and preferred to use thecompounds according to the invention of the formula (I) to treatarteriosclerosis, hypercholesterolaemia and dyslipidaemia. It isadditionally possible to treat adiposity and corpulence (obesity),cardiac arrhythmias and heart failure, and achieve a postprandialreduction in triglycerides.

[0166] The compounds are also suitable for the treatment of certainairway disorders, in particular pulmonary emphysemas, and for medicallypromoting maturation of the lungs.

[0167] The compounds are also suitable for treatment of Alzheimer'sdisease.

[0168] The compounds are furthermore suitable for the treatment ofosteoporosis.

[0169] The compounds can additionally be employed for the promotion andregeneration of hair growth and for the treatment of glaucoma.

[0170] The active substances according to the invention open up afurther treatment alternative and represent an enrichment of pharmacy.Compared with known and previously employed thyroid hormone products,the compounds according to the invention show an improved range ofaction. They are preferably distinguished by great specificity, goodtolerability and fewer side effects, in particular in the cardiovasculararea.

[0171] Administration forms suitable for administering the compounds ofthe general formula (I) are all conventional ones, that is to say oral,parenteral, inhalation, nasal, sublingual, rectal or externals, such as,for example, transdermal, particularly preferably oral or parenteral. Inconnection with parenteral administration, particular mention should bemade of intravenous, intramuscular, subcutaneous administration, forexample as subcutaneous depot. Oral administration is very particularlypreferred.

[0172] The active substances can in this connection be administeredalone or in the form of pharmaceutical preparations. Preparationssuitable for oral administration are, inter alia, tablets, capsules,pellets, coated tablets, pills, granules, solid and liquid aerosols,syrups, emulsions, suspensions and solutions. The active substance mustbe present in an amount such that a therapeutic effect is achieved. Ingeneral, the active substance can be present in a concentration of from0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferablyfrom 5 to 80% by weight. The concentration of active substance should,in particular, be 0.5-90% by weight, that is to say the active substanceshould be present in amounts sufficient to reach the stated dose range.

[0173] For this purpose, the active substances can be converted in amanner known per se into the customary preparations. This takes place byuse of inert, nontoxic, pharmaceutically acceptable carriers,excipients, solvents, vehicles, emulsifiers and/or dispersants.

[0174] Examples of excipients which may be mentioned are: water,nontoxic organic solvents such as, for example, paraffins, vegetableoils (for example sesame oil), alcohols (for example ethanol, glycerol),glycols (for example polyethylene glycol), solid carriers such asnatural or synthetic ground minerals (for example talc or silicates),sugars (for example lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and lubricants (for example magnesium sulphate).

[0175] In the case of oral administration, tablets can, of course, alsocontain additions such as sodium citrate together with additives such asstarch, gelatin and the like. Aqueous preparations for oraladministration may furthermore include flavour improvers or colorants.

[0176] The dosages administered on oral administration are preferablyfrom 0.001 to 5 mg/kg, preferably 0.005 to 3 mg/kg, of body weight every24 hours.

[0177] The activity of the compounds according to the invention can betested for example in vitro by the known T 3 promoter assay cell testwhich is described below.

[0178] The following examples are intended to explain the invention byway of example without having a restricted effect on the scope ofprotection. DMF dimethylformamide DIEA ethyldiisopropylamine DMSOdimethyl sulphoxide TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate DCMdichloromethane TFA trifluoroacetic acid HPLC high performance liquidchromatography RP reversed phase RT room temperature ESI electrosprayionization

[0179] T 3 Promoter Assay Cell Test

[0180] The test is carried out with a stably transfected human HepG2hepatocarcinoma cell which expresses a luciferase gene under the controlof a thyroid hormone-regulated promoter. The vector used for thetransfection has upstream of the luciferase gene a minimal thymidinekinase promoter with a thyroid hormone-responsive element (TRE) whichconsists of two inverted palindromes each of 12 bp and of an 8 bpspacer.

[0181] For the test, the cell cultures are seeded in Eagle's minimalessential medium in 96-well plates with the following additions:glutamine, tricine, sodium pyruvate, nonessential amino acids, insulin,selenium and transferrin. The cultures are grown at 37° C. with a 10%CO₂ atmosphere for 48 hours. In serial dilutions of test substance orreference compound (triiodothyronine=T3, thyroxine=T4) and costimulatorretinoic acid are added to the test cultures and the latter areincubated as previously for a further 48 or 72 hours. Each substanceconcentration is tested in four replicates. To determine the luciferaseinduced by T3 or other substances, the cells are subsequently lysed byadding a Triton- and luciferin-containing buffer and measuredimmediately in a luminometer. The EC₅₀ values for each compound arecalculated (see Table 1). TABLE 1 Example EC₅₀ [nM] 8 20 16 28 29 2.4 546.7 122 55 190 14 204 61 260 12

[0182] The compounds according to the invention also show surprisinglyadvantageous properties in the in vivo test described below:

[0183] Description of Test for Finding Pharmacologically ActiveSubstances Which Lower the Serum Cholesterol in Mice:

[0184] The substances to be investigated for their serumcholesterol-lowering effect in vivo are administered orally to male micewith a body weight between 25 and 35 g. One day before starting thetest, the animals are divided into groups with an identical number ofanimals, usually n=7-10. Throughout the test drinking water and feed areavailable ad libitum to the animals. The substances are administeredorally once a day for 7 days. For this purpose, the test substances aredissolved in a solution of Solutol HS 15+ethanol+saline (0.9%) in theratio 1+1+8 or in a solution of Solutol HS 15+saline (0.9%) in the ratio2+8. The dissolved substances are administered by gavage in a volume of10 ml/kg of body weight. Animals treated in exactly the same way butreceiving only the solvent (10 ml/kg of body weight) without testsubstance serve as control group.

[0185] Before the first administration of substance, blood is taken fromeach mouse by puncture of the retroorbital venous plexus fordetermination of the serum cholesterol (initial value). The testsubstance is then administered to the animals by gavage for the firsttime. 24 hours after the last administration of substance (on the 8thday after the start of treatment), blood is again taken from each animalby puncture of the retroorbital venous plexus for determination of theserum cholesterol. The blood samples are centrifuged and, after theserum is obtained, the cholesterol is determined by photometry using anEPOS analyser 5050 (Eppendorf-Geratebau, Netheler & Hinz GmbH, Hamburg).The determination takes place with a commercially available enzyme assay(Boehringer Mannheim, Mannheim).

[0186] The effect of the test substances on the serum cholesterolconcentration is determined by subtracting the cholesterol level in the1st blood sample (initial value) from the cholesterol level in the 2ndsample (after treatment). The differences of all the cholesterol levelsin a group are averaged and compared with the average of the differencesin the control group.

[0187] Statistical analysis takes place using Student's t test afterprevious checking of the variants for homogeneity.

[0188] Substances which reduce the serum cholesterol in the treatedanimals compared with the control group statistically significantly (p<0.05) by at least 10% are judged as pharmacologically active.

[0189] Attachment of 5-benzoyloxy-2-hydroxybenzaldehyde to Wang BromideResin

[0190] Wang bromide resin (32.0 g, 45.8 mmol, NovaBiochem) is suspendedin acetonitrile/dioxane (1:1, 300 ml) and, after addition ofdiisopropylethylamine (17.7 g, 3.00 eq), caesium iodide (5.94 g, 0.50eq), 18-crown-6 (6.05 g, 0.50 eq) and 5-benzoyloxy-2-hydroxybenzaldehyde(14.4 g, 1.3 eq) [J. G. Bruno, M. N. Chang, Y. M. Choi-Sledeski, D. M.Green, D. G. McGarry, J. R. Regan, F. A. Volz, J.Org.Chem. (1997), 62,5174-5190], shaken at 55° C. for 20 h. The reaction mixture is filteredand the resulting resin 1 is washed repeatedly with water, methanol, DCMand diethyl ether and dried. The loading is determined by eliminationwith TFA/DCM, 1:1, from a resin sample. A loading of 1.35 mmol/g5-benzoyloxy-2-hydroxybenzaldehyde is found by quantitative HPLC.

[0191] Solid-phase Ester Hydrolysis

[0192] Resin 1 (32.0 g) is suspended in dioxane (180 ml) and, afteraddition of a solution of KOH (5.13 g, 2 eq) in methanol (60 ml), shakenat room temperature for 15 minutes. The resulting resin 2 is filteredand washed repeatedly with methanol, water, methanol, DCM and diethylether and dried.

[0193] Solid-phase Formation of the Phenyl Ether

[0194] Resin 2 (32 g) is suspended in DMSO (300 ml) and reacted withCs₂CO₃ (29.8 g, 2 eq), 18-crown-6 (12.1 g, 1 eq) and2-fluoro-1,3-dimethyl-5-nitrobenzene (11.6 g, 1.5 eq) at 40° C. for 1 h.The resin is then washed repeatedly with water/DMF (1:1), water, DMF,methanol, DCM and diethyl ether and dried.

[0195] Preparation of a library Ia

[0196] This and the following libraries are prepared in MiniKans (IRORI)by the mix and split method [K. C. Nicolaou, X.-Y. Xiao, Z. Parandoosh,A. Senyei, M. P. Nova, Angew. Chem. Int. Ed. Engl. (1995), 35,2289-2290].

[0197] Preparation of the library Ia is depicted by way of example indiagram 1.

[0198] Resin 3 is suspended in DCM/DMF, 2:1 in IRORI MiniKans (about 120mg/Kan in each case) and washed repeatedly with DCM and diethyl etherand dried.

[0199] The resin compartmented in this way is suspended in DCM/trimethylorthoformate (1:1) in separate reaction vessels to each of which anamine (5 eq, “amine A”) is added at room temperature and shaken for 18h. The resin in the separate reaction vessels is washed several timeswith DMF and suspended in DMF and, at room temperature,tetrabutylammonium borohydride (2 eq) is added. After shaking at roomtemperature for 5 minutes, the reaction mixture is cooled to −40° C.and, after addition of glacial acetic acid (100 eq), warms to roomtemperature again. The resin is washed repeatedly with water, methanol,DCM/10% of DIEA, methanol, DCM and diethyl ether and dried. The resin isresuspended in dioxane in separate reaction vessels and, after additionof DIEA (20 eq), tetrabutylammonium iodide (2 eq) and alkyl or benzylhalide (10 eq each, “halide B”), stirred at 70° C. for 18 h. Tosynthesize secondary amines (R⁷=H), in place of the alkylation the resinis suspended in dioxane/2-propanol, 3/1, and, after addition oftriethylamine (2 eq) and bis-tert-butyl pyrocarbonate (10 eq), shaken atRT for 2 h.

[0200] The resin is filtered again and washed repeatedly with water,DMF, methanol, DCM and diethyl ether and dried. The resin is suspendedin DMF/water, 9:2, and, after addition of tin(II) chloride dihydrate (5eq), reacted at 60° C. for 2 hours and washed repeatedly with water,DMF, methanol, DCM and diethyl ether. The resin compartments are againdistributed to separate reaction vessels, suspended in DCM and reactedwith DIEA (10 eq) and various acid chlorides or chloroformic esters (5eq of each “acid chloride C”) at room temperature for 18 h. The resin isreacted analogously in a reaction vessel with ethyl bromoacetate (5 eq)at 40° C. overnight. The resin is finally washed repeatedly withmethanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried.The products are then cleaved off the solid phase withTFA/dichloromethane (1:1), the resin is filtered off, and the reactionsolutions are evaporated in order to obtain a set of amines Ia.

[0201] Rx corresponds to a radical of the formula CH₃CO—, C₂H₅OOCCH₂— orC₂H₅OOCCO—, Y corresponds to a suitable leaving group such as, forexample, Cl, Br.

[0202] Preparation of the library Ib is depicted by way of example indiagram 2.

[0203] Resin 3 is suspended in DCM/DMF, 2:1, in IRORI MiniKans (in eachcase about 120 mg/Kan) and washed repeatedly with DCM and diethyl etherand dried.

[0204] The resin compartmented in this way is suspended in DCM/trimethylorthoformate (1: 1) in separate reaction vessels to each of which anamine (5 eq, “amine A”) is added at room temperature and shaken for 18h. The resin in the separate reaction vessels is washed several timeswith DMF and suspended in DMF and, at room temperature,tetrabutylammonium borohydride (2 eq) is added. After shaking at roomtemperature for 5 minutes, the reaction mixture is cooled to −40° C.and, after addition of glacial acetic acid (100 eq), warmed to roomtemperature again. The resin is washed repeatedly with 20% glacialacetic acid in methanol, water, DMF, 10% triethylamine in DCM, DCM anddiethyl ether and dried. The resin is again suspended in DCM in separatereaction vessels and, after addition of DIEA (10 eq) and one acidchloride (5 eq, “acid chloride B”) in each case, shaken at roomtemperature for 2 h. The resin is filtered and washed repeatedly withmethanol, DCM and diethyl ether and dried. The resin is suspended inDMF/water, 9:2, and, after addition of tin(II) chloride dihydrate (5eq), reacted at 40° C. for 4 hours and washed repeatedly with water,DMF, methanol, DCM and diethyl ether. The resin compartments are againdistributed to separate reaction vessels, suspended in DCM and reactedwith DIEA (10 eq) and in each case one acid chloride or chloroformicester (5 eq, “acid chloride C”) at room temperature for 18 h. The resinis reacted analogously in a reaction vessel with ethyl bromoacetate (5eq) at 40° C. overnight. The resin is finally washed repeatedly withmethanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried.The products are then cleaved off the solid phase withTFA/dichloromethane (1:1), the resin is filtered off, and the reactionsolutions are separated in order to obtain a set of amides Ib.

[0205] R^(X) corresponds to a radical of the formula CH₃CO—, C₂H₅OOCCH₂—or C₂H₅OOCCO—, Y corresponds to a suitable leaving group such as, forexample, Cl, Br.

[0206] Wang bromide resin (25.0 g, 35.0 mmol, NovaBiochem) is suspendedin dimethylacetamide (150 ml) and, after addition ofdiisopropylethylamine (22.6 g, 5.0 eq), caesium iodide (4.55 g, 0.50 eq)and 4-hydroxy-3-nitrophenyl benzoate (27.2 g, 3.0 eq) [M. Svensson, B.Helgee, K. Skarp, G. Andersson, J.Mater.Chem.(1998), 8, 353-362], shakenat room temperature overnight. The reaction mixture is filtered and theresin 4 is washed repeatedly with methanol, water, DMF, methanol, DCMand diethyl ether and dried. The loading is determined by eliminationwith TFA/DCM 1:1, from a resin sample. A loading of 0.87 mmol/g4-benzoyloxy-2-nitrophenol is found by quantitative HPLC.

[0207] Reduction of the Nitro Group on Resin 4

[0208] Resin 4 (60 g) is suspended with tin(II) chloride dihydrate (94.8g, 420 mmol) in DMF/water, 9: 1, and stirred at 60° C. for 2 h. Thereaction mixture is filtered and the resin 5 is washed repeatedly withwater, methanol, DCM and diethyl ether and dried.

[0209] Preparation of a Library Ic

[0210] Resin 5 is suspended in DCM/DMF, 2:1, in IRORI MiniKans (in eachcase about 120 mg/Kan) and washed repeatedly with DCM and diethyl etherand dried.

[0211] a) Preparation of amides and urethanes (R¹⁰—NR¹⁴R¹⁵)

[0212] Preparation of the amide library Ic is depicted by way of examplein diagram 3.

[0213] The compartmented aniline resin is suspended in DCM in separatereaction vessels, and DIEA (10 eq) and in each case one acid chloride (5eq, “acid chloride A”) are added at 0° C.—room temperature. Thisreaction mixture is shaken at room temperature overnight. The resin iswashed repeatedly with methanol, DCM and diethyl ether and dried. Theresin is mixed with a solution of potassium hydroxide (2 eq) indioxane/methanol (2:1) and shaken at room temperature for 45 minutes,filtered and washed repeatedly with methanol, DCM and diethyl ether anddried. The resin is suspended in DMSO and reacts with caesium carbonate(3 eq), 18-crown-6 (1 eq) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (5eq) at 55° C. for 60 h. The resin is then washed repeatedly with water,DMF, methanol, DCM and diethyl ether and dried. The resin is suspendedin DMF/water, 9:2, and, after addition of tin(II) chloride dihydrate (5eq), reacted at 60° C. for 90 minutes and washed repeatedly withmethanol, DCM and diethyl ether. The resin compartments are againdistributed to separate reaction vessels, suspended in DCM and reactedwith DIEA (10 eq) and various acid chlorides or chloroformic esters (5eq, “acid chloride B”) at room temperature for 6 h. The resin in onereaction vessel is reacted analogously with ethyl bromoacetate (5 eq) at40° C. overnight. The resin is finally washed repeatedly with methanol,DMF, water, DMF, methanol, DCM and diethyl ether and dried. The productsare then cleaved off the solid phase with TFA/dichloromethane (1:1), theresin is filtered off, and the reaction solutions are evaporated toobtain a set of amides Ic.

[0214] R^(X) corresponds to a radical of the formula, CH₃CO—,C₂H₅OOCCH₂— or C₂H₅OOCCO—, Y corresponds to a suitable leaving groupsuch as, for example, Cl, Br.

Diagram 3

[0215] b) Preparation of ureas (R¹⁰=NR¹⁴R¹ ⁵) Ic

[0216] Preparation of the urea library Ic is depicted by way of examplein diagram 4.

[0217] The compartmented aniline resin is suspended in DCM in separatereaction vessels and, after addition of DIEA (15 eq), cooled to —20 to-30° C. Trichloromethyl chloroformate (1.5 eq) is added and stirred at—20° C. for 1 h. While cooled, in each case primary or secondary amines(10 eq, “amine 1”) are added and shaken at room temperature overnight.The resin is washed repeatedly with methanol, DCM and diethyl ether anddried. The resin is mixed with a solution of potassium hydroxide (2 eq)in dioxane/methanol (2:1) and shaken at room temperature for 45 minutes,filtered and washed repeatedly with methanol, DCM and diethyl ether anddried. The resin is suspended in DMSO and reacted with caesium carbonate(3 eq), 18-crown-6 (1 eq) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (5eq) at 55° C. for 60 h. The resin is then washed repeatedly with water,DMF, methanol, DCM and diethyl ether and dried. The resin is suspendedin DMF/water, 9:2, and, after addition of tin(II) chloride dihydrate (5eq), reacted at 60° C. for 90 minutes and washed repeatedly withmethanol, DCM and diethyl ether. The resin compartments are againdistributed to separate reaction vessels, suspended in DCM and reactedwith DIEA (10 eq) and in each case one acid chloride or chloroformicester (5 eq, “acid chloride B”) at room temperature for 6 h. The resinin one reaction vessel is reacted analogously with ethyl bromoacetate (5eq) at 40° C. overnight. The resin is finally washed repeatedly withmethanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried.The products are then cleaved off the solid phase withTFA/dichloromethane (1:1), the resin is filtered off, and the reactionsolutions are evaporated to obtain a set of ureas Ic.

[0218] R^(X) corresponds to a radical of the formula CH₃CO—, C₂H₅OOCCH₂—or C₂H₅OOCCO—, Y corresponds to a suitable leaving group such as, forexample, Cl, Br.

[0219] 5-Benzoyloxy-2-hydroxybenzoic acid [M. Bergmann, P. Dangschat,Chem Ber. (1919), 52, 371-387] (2.00 g, 7.74 mmol) is suspended in DMF(10 ml), and diisopropylethylamine (1.20 g, 9.29 mmol), caesium iodide(0.201 g, 0.77 mmol) and iodoethane (2.42 g, 15.5 mmol) are added. Thereaction mixture is stirred at room temperature overnight and taken upin diethyl ether. The organic phase is washed with water, saturatedNaHCO₃ solution, 1 N HCl and saturated NaCl solution, dried with MgSO₄,decanted and evaporated. The crude product is purified by flash columnchromatography on silica gel by petroleum ether/ethyl acetate, 1:0-9:1.

[0220] Yield: 1.96 g (89%) 6.

[0221]¹H-NMR (400 MHz, CDCl₃): 1.41, t, 3H; 4.41, q, 2H; 7.03, d, 1H;7.31, dd, 1H; 7.48-7.55, m, 2H; 7.61-7.68,, 1H; 7.70, d, 1H; 8.19, d,2H; 10.78, s, 1H.

[0222] Attachment of ethyl 5-benzoyloxy-2-hydroxybenzoate (6) to WangBromide Resin

[0223] Wang bromide resin (50.0 g, 70.0 mmol, NovaBiochem) is suspendedin acetonitrile/dioxane (1:1, 300 ml) and, after addition ofdiisopropylethylamine (90.4 g, 10.0 eq), caesium iodide (1.82 g, 0.10eq), 18-crown-6 (18.5 g, 1 eq) and ethyl 5-benzoyloxy-2-hydroxybenzoate(6) (30.1 g, 1.5 eq), shaken at 80° C. overnight. The reaction mixtureis filtered and the resin 7 is washed repeatedly with DMF, water,methanol, DCM and diethyl ether and dried. The loading is determined byelimination with TFA/DCM, 1:1, from a resin sample. A loading of 0.42mmol/g ethyl 5-benzoyloxy-2-hydroxybenzoate (6) is found by quantitativeHPLC.

[0224] Selective Solid-phase Ester Hydrolysis

[0225] Resin 7 (50 g) is suspended in dioxane (260 ml) and, afteraddition of a solution of KOH (4.94 g) in methanol (130 ml), shaken atroom temperature for 5 minutes. The resulting resin 8 is filtered andwashed repeatedly with DMF, 10% glacial acetic acid in DCM, methanol,DCM, diethyl ether and dried.

[0226] Solid-phase Formation of the Phenyl Ether

[0227] Resin 8 (33 g) is suspended in DMSO (300 ml) and reacted withCs₂CO₃ (14.2 g), K18-crown-6 (3.84g) and2-fluoro-1,3-dimethyl-5-nitrobenzene (eq) at 50° C. for 20 h. Theresulting resin 9 is then washed repeatedly with water/DMF (1:1), water,DMF, methanol, DCM and diethyl ether and dried.

[0228] Solid-phase Ester Hydrolysis

[0229] Resin 9 (32 g) is suspended in dioxane (260 ml) and, afteraddition of a solution of KOH (7.90 g) in methanol (130 ml), stirred at50° C. for 1 h. The resulting resin 10 is filtered and washed threetimes with methanol, 10% glacial acetic acid in DCM, methanol, DCM anddiethyl ether and dried.

[0230] Preparation of a Library Id

[0231] Preparation of the library Id is depicted by way of example indiagram 5.

[0232] Resin 10 is suspended in DCM/DMF, 2:1, in IRORI MiniKans (in eachcase about 120 mg/Kan) and washed repeatedly with DCM and diethyl etherand dried.

[0233] The resin compartmented in this way is suspended in DCM inseparate reaction vessels and, after addition of DIEA (10 eq), in eachcase one amine (5 eq, “amine A”) and TBTU (5 eq) at room temperature,shaken overnight. The resin is washed repeatedly with methanol, DCM anddiethyl ether and dried. The resin is suspended in DMF/water, 9:2, and,after addition of tin(II) chloride dihydrate (5 eq), reacted at 40° C.for 4 hours and washed repeatedly with methanol, DCM and diethyl ether.The resin compartments are again distributed to separate reactionvessels, suspended in DCM and reacted with DIEA (10 eq) and in each caseone acid chloride or chloroformic ester (5 eq, “acid chloride B”) atroom temperature for 18 h. The resin in one reaction vessel is reactedanalogously with ethyl bromoacetate (5 eq) at 40° C. overnight. Theresin is washed repeatedly with methanol, DMF, water, DMF, methanol, DCMand diethyl ether and dried. The products are cleaved off the solidphase with TFA/dichloromethane (1:1), the resin is filtered off, and thereaction solutions are evaporated in order to obtain a set ofcarboxamides Id.

[0234] R^(X) corresponds to a radical of the formula CH₃CO—, C₂H₅OOCCH₂—or C₂H₅OOCCO—, Y corresponds to a suitable leaving group such as,example, Cl, Br.

Diagram 5 PREPARATION EXAMPLES Example 1

[0235] Ethyl{[4-(3-{[benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethyl-phenyl]amino}(oxo)acetate

[0236] In accordance with the general procedure for preparing thelibrary Ia, 1.00 g of resin 3 is reacted with isopropylamine as “amineA”, benzyl chloride as “halide B” and ethoxalyl chloride as “acidchloride C”. The resulting crude product is purified by preparativeRP-HPLC with a water/acetonitrile/TFA eluent. This product ispartitioned between saturated NaHCO₃ solution and DCM, and the organicphase is salted out with NaCl, decanted and evaporated.

[0237] Yield: 30 mg of ethyl{[4-(3-{[benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate

[0238]¹H-NMR (200 MHz, CDCl₃): 1.13, d, 6H; 1.44, t, 3H; 2.11, s, 6H;3.09, sept, 1H; 3.60, s, 2H; 3.71, s, 2H; 4.42, q, 2H; 6.40, d, 1H;6.52, dd, 1H; 6.69, d, 1H; 7.20-7.40, m, 7H; 8.77, s, 1H.

Example 2

[0239] Ethyl{[4-(3-{[benzyl(cyclohexyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethyl-phenyl]amino}(oxo)acetate

[0240] In accordance with the general procedure for preparing thelibrary Ia, 1.00 g of resin 3 is reacted with cyclohexylamine as “amineA”, benzyl chloride as “halide B” and ethoxalyl chloride as “acidchloride C”. The resulting crude product is purified by preparativeRP-HPLC with a water/acetonitrile/TFA eluent. This product ispartitioned between saturated NaHCO₃ solution and DCM, and the organicphase is salted out with NaCl, decanted and evaporated.

[0241] Yield: 30mg of ethyl{[4-(3-{[benzyl(cyclohexyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate

[0242]¹H-NMR (200 MHz, CDCl₃): 1.00-1.95, m, 10H; 1.43, t, 3H; 2.12, s,6H; 2.61, m, 1H; 3.64, s, 2H; 3.75, s, 2H; 4.42, q, 2H; 6.39, d, 1H;6.52, dd, 1H; 6.67, d, 1H; 7.20-7.40, m, 7H; 8.77, s, 1H.

Example 3

[0243] Ethyl{[4-(3-{[cyclohexyl(4-fluorobenzyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate

[0244] In accordance with the general procedure for preparing thelibrary Ia, 1.00 g of resin 3 is reacted with cyclohexylamine as “amineA”, 4-fluorobenzyl chloride as “halide B” and ethoxalyl chloride as“acid chloride C”. The resulting crude product is purified bypreparative RP-HPLC with a water/acetonitrile/TFA eluent. This productis partitioned between saturated NaHCO₃ solution and ethyl acetate, andthe ethyl acetate phase is salted out with NaCl, decanted andevaporated.

[0245] Yield: 30 mg of ethyl{[4-(3-{[cyclohexyl(4-fluorobenzyl)amino]methyl}-4-hydroxy-phenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate

[0246]¹H-NMR (200 MHz, CDCl₃): 1.20, d, 6H; 1.44, t, 3H; 2.11, s, 6H;3.20, sept, 1H; 3.68, s, 2H; 3.76, s, 2H; 4.42, q, 2H; 6.40, d, 1H;6.57, dd, 1H; 6.75, d, 1H; 6.95 -7.10, m, 2H; 7.25-7.33, dd, 2H; 7.36,s, 2H; 8.79, s, 1H.

Example 4

[0247]{[4-(3-{[Benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]-amino}(oxo)aceticAcid

[0248] Ethyl{[4-(3-{[benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate(50 mg, 0,10 mmol) and NaOH (40 mg, 1.02 mmol) are dissolved indioxane/water (0.5 1, 1:1 v/v) and stirred at room temperature for 1 h.The reaction mixture is partitioned between ethyl acetate and potassiumdihydrogen phosphate/disodium hydrogen phosphate buffer solution (pH 7),and the organic phase is salted out with NaCl, filtered and evaporated.The resulting crude product is purified by preparative RP-HPLC with awater/acetonitrile/TFA eluent.

[0249] Yield: 23 mg of{[4-(3-{[benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)aceticAcid

[0250] MS: 463.2 [MH⁺]

Example 5

[0251] Ethyl(4-{4-hydroxy-3-[(2-phenoxybutanoyl)amino]phenoxy}-3,5-dimethylanilino)-(oxo)acetate

[0252] In accordance with the general procedure for preparing thelibrary Ic, 1.5 g (0.13 mmol) of resin 5 are reacted with2-phenoxybutyryl chloride as “acid chloride A” and ethoxalyl chloride as“acid chloride B”. The resulting crude product is purified bypreparative RP-HPLC with a water/acetonitrile/TFA eluent.

[0253] Yield: 0.305 g of ethyl(4-{4-hydroxy-3-[(2-phenoxybutanoyl)amino]phenoxy}-3,5-dimethylanilino)(oxo)acetate

[0254]¹H-NMR (400 MHz, CDCl₃): 1.09, t, 3H; 1.43, t, 3H; 1.95-2.12, m,2H; 2.10, s, 6H; 4.42, q, 2H; 4.71, dd, 1H; 6.43, d, 1H; 6.51, dd, 1H;6.90, d, 1H; 6.97, d, 2H; 7.06, t, 1H; 7.31, d, 2H; 7.35, s, 2H; 8.33 s,1H; 8.77, s, 1H.

[0255] MS: 507 [MH⁺].

Example 6

[0256] Ethyl(4-{3-[(biphenyl-4-ylcarbonyl)amino]-4-hydroxyphenoxy}-3,5-dimethylanilino)(oxo)acetate

[0257] In accordance with the general procedure for preparing thelibrary Ic, the resin 5 is reacted with biphenyl-4-ylcarbonyl chlorideas “acid chloride A” and ethoxalyl chloride as “acid chloride B”. Theresulting crude product is purified by preparative RP-HPLC with awater/acetonitrile eluent.

[0258] Yield: 6.4mg of ethyl(4-{3-[(biphenyl-4-ylcarbonyl)amino]-4-hydroxyphenoxy}-3,5-dimethylanilino)(oxo)acetate

[0259]¹H-NMR (200 MHz, CDCl₃): 1.41, t, 3H; 2.13, s, 6H; 4.42, q, 2H;6.53, d, 1H; 6.69, dd, 1H; 7.01, d, 1H; 7.34, s, 2H; 7.38-7.75, m, 7H;7.96, d, 2H; 8.18, s, 1H; 8.80, s, 1H.

[0260] MS: 525 [MH⁺].

Example 7

[0261] Ethyl(4-{3-[(cyclopropylcarbonyl)amino]-4-hydroxyphenoxy}-3,5-dimethylanilino)-(oxo)acetate

[0262] In accordance with the general procedure for preparing thelibrary Ic, the resin 5 is reacted with cyclopropylcarbonyl chloride as“acid chloride A” and ethoxalyl chloride as “acid chlorid B”. Theresulting crude product is purified by preparative RP-HPLC with awater/acetonitrile eluent.

[0263] Yield: 9.0 mg of ethyl(4-{3-[(cyclopropylcarbonyl)amino]-4-hydroxyphenoxy}-3,5-dimethylanilino)(oxo)acetate

[0264]¹H-NMR (200 MHz, CDCl₃): 0.83-0.97, m, 2H; 1.05-1.17, m, 2H; 1.41,t, 3H; 1.52-1.68, m, 1H; 2.10, s, 6H; 4.40, q, 2H; 6.27, d, 1H; 6.66,dd, 1H; 6.93, d, 1H; 7.31, s, 2H; 7.93, s, 1H; 8.35, s, 1H.

[0265] MS: 413 [MH⁺].

Example 8

[0266] Ethyl(4-{4-hydroxy-3-[(3-phenylpropanoyl)amino]phenoxy}-3,5-dimethylanilino)-(oxo)acetate

[0267] In accordance with the general procedure for preparing thelibrary Ic, the resin 5 is reacted with 3-phenylpropionyl chloride as“acid chloride A” and ethoxalyl chloride as “acid chloride B”. Theresulting crude product is purified by preparative RP-HPLC with awater/acetonitrile eluent.

[0268] Yield: 12.0 mg of ethyl(4-{4-hydroxy-3-[(3-phenylpropanoyl)amino]phenoxy}-3,5-dimethylanilino)(oxo)acetate

[0269]¹H-NMR (200 MHz, CDCl₃): 1.38, t, 3H; 2.09, s, 6H; 2.70, t, 2H;3.03, t, 2H; 4.39, q, 2H; 6.10, d, 1H; 6.65, dd, 1H; 6.92 d, 1H;7.12-7.33, m, 5H; 7.32, s, 2H; 7.56, s, 1H; 8.83, s, 1H. MS: 477 [MH⁺].

Example 9

[0270] Ethyl(4-{4-hydroxy-3-[(2-phenylbutanoyl)amino]phenoxy}-3,5-dimethylanilino)-(oxo)acetate

[0271] In accordance with the general procedure for preparing thelibrary Ic, 1.5 g (0.13 mmol) of resin 5 are reacted with2-phenylbutyryl chloride as “acid chloride A” and ethoxalyl chloride as“acid chloride B”. The resulting crude product is purified bypreparative RP-HPLC with a water/acetonitrile eluent.

[0272] Yield: 4.2 mg of ethyl(4-{4-hydroxy-3-[(2-phenylbutanoyl)amino]phenoxy}-3,5-dimethylanilino)(oxo)acetate

[0273]¹H-NMR (200 MHz, CDCl₃): 0.91, t, 3H; 1.36, t, 3H; 1.73-2.00, m,1H; 2.08, s, 6 H; 2.12-2.33, m, 1H; 3.46, t, 1H; 4.35, q, 2H; 6.29, d,1H; 6.55, dd, 1H; 6.89, d, 1H; 7.22-7.40, m, 5H; 7.35, s, 2H; 7.61, s,1H; 8.23, br s, 1H; 8.80, s, 1H.

[0274] MS: 491 [MH⁺].

Example 10

[0275] Ethyl{4-[3-(hexanoylamino)-4-hydroxyphenoxy]-3,5-dimethylanilino}(oxo)acetate

[0276] In accordance with the general procedure for preparing thelibrary Ic, 1.5 g (0.13 mmol) of resin 5 are reacted with hexanoylchloride as “acid chloride A” and ethoxalyl chloride as “acid chlorideB”. The resulting crude product is purified by preparative RP-HPLC witha water/acetonitrile eluent.

[0277] Yield: 8.6 mg of ethyl{4-[3-(hexanoylamino)-4-hydroxyphenoxy]-3,5-dimethylanilino}(oxo)acetate

[0278]¹H-NMR (200 MHz, CDCl₃): 0,89, t, 3H; 1.22-1.42, m, 4H; 1.40, t,3H; 1.60- 1.80, m, 2H; 2.10, s, 6H; 2.38, t, 2H; 4.40, q, 2H; 6.29, d,1H; 6.66, dd, 1H; 6.93, d, 1H; 7.31, s, 2H; 7.72, s, 1H; 8.4, br s, 1H;8.84, s, 1H.

[0279] MS: 443 [MH⁺].

Example 11

[0280] Ethyl(4-{4-hydroxy-3-[(2-propylpentanoyl)amino]phenoxy}-3,5-dimethylanilino)-(oxo)acetate

[0281] In accordance with the general procedure for preparing thelibrary Ic, 1.5 g (0.13 mmol) of resin 5 are reacted with2-propylpentanoyl chloride as “acid chloride A” and ethoxalyl chlorideas “acid chloride B”. The resulting crude product is purified bypreparative RP-HPLC with a water/acetonitrile eluent.

[0282] Yield: 11.5 mg of ethyl(4-{4-hydroxy-3-[(2-propylpentanoyl)amino]phenoxy}-3,5-dimethylanilino)(oxo)acetate

[0283]¹H-NMR (200 MHz, CDCl₃): 0,90, t, 6H; 1.20-1.80, m, 8H; 1.37, t,3H; 2.23-2.43, m, 1H; 4.38, q, 2H; 6.32, d, 1H; 6.63, dd, 1H; 6.93, d,1H; 7.32, s, 2H; 7.85, S, 1H; 8.85, s, 1H.

[0284] MS: 471 [MH⁺].

Example 12

[0285] Ethyl(4-{4-hydroxy-3-[(methoxyacetyl)amino]phenoxy}-3,5-dimethylanilino)-(oxo)acetate

[0286] In accordance with the general procedure for preparing thelibrary Ic, 1.5 g (0.13 mmol) of resin 5 are reacted with methoxyacetylchloride as “acid chloride A” and ethoxalyl chloride as “acid chlorideB”. The resulting crude product is purified by preparative RP-HPLC witha water/acetonitrile eluent.

[0287] Yield: 13.7 mg of ethyl(4-{4-hydroxy-3-[(methoxyacetyl)amino]phenoxy}-3,5-dimethylanilino)(oxo)acetate

[0288]¹H-NMR (200 MHz, CDCl₃): 1.44, t, 3H; 2.12, s, 6H; 3.51, s, 3H;4.16, s, 2H; 4.42, q, 2H; 6.39, d, 1H; 6.61, dd, 1H; 6.93, d, 1H; 7.38,s, 2H; 8.28, s, 1H; 8.38, t, 1H; 8.80, s, 1H.

[0289] MS: 417 [MH⁺].

Example 13

[0290]N-{5-[4-(Acetylamino)-2,6-dimethylphenoxy]-2-hydroxyphenyl}-2-phenoxybutanamide

[0291] In accordance with the general procedure for preparing thelibrary Ic, the resin 5 is reacted with 2-phenoxybutyryl chloride as“acid chloride A” and acetyl chloride as “acid chloride B”. Theresulting crude product is purified by preparative RP-HPLC with awater/acetonitrile eluent.

[0292] Yield: 11.3 mg ofN-{5-[4-(acetylamino)-2,6-dimethylphenoxy]-2-hydroxyphenyl}-2-phenoxybutanamide

[0293]¹H-NMR (200 MHz, CDCl₃): 1.08, t, 3H; 1.98-2.10, m, 2H; 2.05, s,6H; 2.13, s, 3 H; 4.70, dd, 1H; 6.47-6.57, m, 2H; 6.83-7.40, m, 8H;7.97, s, 1H; 8.52, s, 1H.

[0294] MS: 449 [MH⁺].

Example 14

[0295] Ethyl{4-[4-hydroxy-3-({[(1-phenylethyl)amino]carbonyl}amino)phenoxy]-3,5-dimethylanilino}(oxo)acetate

[0296] In accordance with the general procedure for preparing thelibrary Ic, the resin resin 5 is reacted with 1-phenylethylamine as“amine A” and ethoxalyl chloride as “4acid chloride B”. The resultingcrude product is purified by preparative RP-HPLC with awater/acetonitrile eluent.

[0297] Yield: 9.0 mg of ethyl{4-[4-hydroxy-3-({[(1-phenylethyl)amino]carbonyl}amino)-phenoxy]-3,5-dimethylanilino}(oxo)acetate¹H-NMR (200 MHz, CDCl₃): 1.41, t, 3H; 1.46, t, 3H; 2.03, s, 6H; 4.41, q,2H; 4.82, dq, 1H; 5.32, d, 1H; 5.95, d, 1H; 6.53, dd, 1H; 6.6, s, 1H;6.85, d, 1H; 7.20-7.40, m, 7H; 8.88, s, 1H.

[0298] MS: 492 [MH⁺].

Example 15

[0299] Ethyl[4-(3-{[(cyclohexylmethyl)amino]carbonyl}-4-hydroxyphenoxy)-3,5-dimethyl-anilino](oxo)acetate

[0300] In analogy to the general procedure for preparing the library Id,2.00 g of of resin 10 are reacted with (cyclohexylmethyl)amine as “amineA” and ethoxalyl chloride as “acid chloride B”. The resulting crudeproduct is purified by preparative RP-HPLC with a water/acetonitrileeluent.

[0301] Yield: 95 mg of ethyl[4-(3-{[(cyclohexylmethyl)amino]carbonyl}-4-hydroxyphenoxy)-3,5-dimethylanilino](oxo)acetate

[0302]¹H-NMR (200 MHz, CDCl₃): 0.85-1.83, m, 11H; 1.44, t, 3H; 2.14, s,6H; 3.27, t, 2H; 4.42, q, 1H; 6.29, t, 1H; 6.70-6.92, m, 3H; 7.40, s,2H; 8.80, s, 1H.

Example 16

[0303] Ethyl[4-(3-{[cyclohexyl(methyl)amino]carbonyl}-4-hydroxyphenoxy)-3,5-dimethylanilino](oxo)acetate

[0304] In analogy to the general procedure for preparing the library Id,2.00 g of of resin 10 are reacted with cyclohexyl(methyl)amine as “amineA” and ethoxalyl chloride as “acid chloride B”. The resulting crudeproduct is purified by preparative RP-HPLC with a water/acetonitrileeluent.

[0305] Yield: 30 mg of ethyl[4-(3-{[cyclohexyl(methyl)amino]carbonyl}-4-hydroxyphenoxy)-3,5-dimethylanilino](oxo)acetate

[0306]¹H-NMR (200 MHz, CDCl₃): 0.95-1.83, m, 10H; 1.44, t, 3H; 2.12, s,6H; 2.89, s, 3H; 4.42, q, 1H; 6.50, d, 1H; 6.86, dd, 1H; 6.93, d, 1H;7.39, s, 2H; 8.80, s, 1H.

[0307] The compounds listed below are prepared in accordance with thegeneral procedures for libraries Ia-Id.

[0308] Analytical Parameters

[0309] All the products are characterized by LC-MS. The standardseparation system used for this is as follows: HP 1100 with UV detector(208-400 nm), 40° C. oven temperature, Waters-Symmetry C18 column (50 mmx 2.1 mm, 3,5 μm), mobile phase A: 99.9% acetonitrile/0.1% formic acid,mobile phase B: 99.9% water/0.1% formic acid; gradient: Time Flow rate(min) A:% B:% (ml/min) 0.00 10.0 90.0 0.50 4.00 90.0 10.0 0.50 6.00 90.010.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50

[0310] The substances were detected using a Micromass Quattro LCZ MS,ionization: ESI positive/negative. MW Retention MW [g/mol] time [g/mol]Ex. No. Structure calculated [min] found 17

398.5 2.64 398.2 18

428.5 2.78 428.2 19

442.6 2.90 442.2 20

442.6 2.88 442.2 21

442.6 2.93 442.2 22

442.6 3.36 442.2 23

456.6 2.99 456.3 24

476.6 3.01 476.2 25

484.6 3.23 484.3 26

484.6 3.28 484.3 27

484.6 3.28 484.3 28

490.6 3.08 490.2 29

490.6 3.13 490.2 30

490.6 3.13 490.2 31

494.6 3.06 494.2 32

496.7 3.66 496.3 33

496.7 496.3 34

498.7 3.34 498.3 35

504.6 3.34 504.3 36

504.6 3.59 504.3 37

504.6 3.17 504.3 38

504.6 3.08 504.3 39

508.6 3.61 508.2 40

508.6 3.19 508.2 41

511.6 3.35 511.3 42

519.6 3.05 519.3 43

520.6 3.56 520.3 44

523.6 3.11 523.2 45

528.6 4.08 528.2 46

531.7 3.19 531.3 47

532.6 5.39 532.3 48

532.7 3.51 532.3 49

532.7 3.51 532.3 50

533.6 3.29 533.3 51

533.7 3.84 533.3 52

538.6 3.70 538.2 53

538.6 5.42 538.2 54

538.6 3.89 538.2 55

538.7 3.94 538.3 56

538.7 538.3 57

539.6 3.73 539.2 58

542.6 4.19 542.2 59

542.6 5.47 542.2 60

544.7 544.3 61

544.7 3.98 544.3 62

546.6 4.45 546.2 63

546.7 5.41 546.3 64

546.7 3.49 546.3 65

547.7 3.40 547.3 66

548.7 3.64 548.3 67

549.6 3.34 549.3 68

550.6 5.55 550.2 69

550.7 3.57 550.3 70

552.7 3.49 552.3 71

553.7 3.60 553.3 72

556.6 4.01 556.2 73

557.6 3.96 557.2 74

559.5 3.64 558.2 75

559.5 3.54 558.2 76

558.7 3.95 558.3 77

559.7 3.69 559.3 78

560.7 3.53 560.3 79

562.7 4.23 562.3 80

566.7 3.70 566.3 81

571.7 3.65 571.2 82

573.5 3.47 572.2 83

573.5 4.23 572.2 84

574.7 3.73 574.3 85

576.7 3.15 576.3 86

577.7 3.42 577.3 87

577.7 4.00 577.3 88

578.7 3.69 578.3 89

581.7 4.77 581.3 90

585.7 3.64 585.2 91

592.7 3.86 592.3 92

592.7 3.74 592.3 93

594.8 594.4 94

596.7 3.77 596.3 95

601.6 4.15 600.2 96

601.7 3.71 601.3 97

601.8 601.4 98

602.8 3.98 602.4 99

607.5 5.05 606.2 100

613.6 612.2 101

619.8 5.42 619.3 102

621.6 4.30 620.2 103

625.5 5.14 624.2 104

635.6 4.11 634.2 105

658.8 5.01 658.4 106

476.5 4.30 476.2 107

482.6 4.53 482.2 108

494.5 4.26 494.2 109

503.6 4.24 503.2 110

520.6 4.59 520.2 111

522.6 4.63 522.2 112

522.6 4.96 522.3 113

524.7 5.08 524.3 114

536.6 4.83 536.2 115

538.7 5.16 538.3 116

539.6 4.38 539.2 117

544.7 4.78 544.3 118

553.1 4.52 552.2 119

556.6 4.55 556.2 120

568.7 5.07 568.3 121

576.7 5.22 576.3 122

578.7 5.40 578.3 123

328.4 2.83 328.2 124

332.3 4.19 332.1 125

342.4 3.18 342.2 126

368.3 4.40 368.1 127

368.5 3.42 368.2 128

368.5 3.47 368.2 129

370.4 3.81 370.2 130

370.5 3.62 370.2 131

376.5 3.13 376.2 132

378.4 4.58 378.1 133

386.4 3.56 386.1 134

390.5 3.42 390.2 135

394.3 3.71 394.1 136

400.4 3.85 400.2 137

406.5 3.41 406.2 138

410.5 4.26 410.2 139

412.5 4.41 412.2 140

412.5 4.42 412.2 141

414.5 4.05 414.2 142

414.5 4.05 414.2 143

417.3 3.29 416.1 144

418.5 4.02 418.3 145

428.5 4.27 428.2 146

428.5 4.23 428.2 147

428.5 4.24 428.2 148

428.5 4.75 428.2 149

432.5 4.22 432.2 150

440.3 4.30 440.0 151

442.5 4.44 442.2 152

446.5 4.09 446.2 153

448.5 4.19 448.2 154

448.5 4.19 448.2 155

448.5 4.53 448.2 156

449.5 4.14 449.2 157

454.5 4.47 454.2 158

456.5 4.68 456.2 159

464.5 4.45 464.2 160

464.5 4.50 464.2 161

464.6 4.64 464.2 162

468.5 4.68 468.2 163

470.6 4.89 470.2 164

476.5 4.41 476.2 165

476.5 4.17 476.3 166

478.5 4.29 478.2 167

478.6 4.81 478.2 168

480.6 4.97 480.2 169

482.6 4.43 482.2 170

484.5 4.77 484.2 171

486.3 4.62 486.1 172

490.6 4.55 490.2 173

490.6 4.65 490.2 174

492.5 4.41 492.2 175

496.6 4.61 496.3 176

498.5 4.48 498.2 177

499.0 4.56 498.2 178

500.6 4.74 500.2 179

502.6 5.12 502.2 180

504.5 4.49 504.2 181

504.6 4.68 504.2 182

514.6 4.99 514.2 183

516.5 4.58 516.2 184

516.6 4.70 516.2 185

518.6 4.54 518.2 186

527.0 4.96 526.2 187

527.0 4.96 526.2 188

534.6 4.51 534.2 189

540.6 5.00 540.2 190

541.0 4.80 540.2 191

541.0 4.80 540.2 192

542.6 4.94 542.3 193

555.0 4.65 554.2 194

559.4 4.85 558.1 195

559.4 4.61 558.1 196

564.6 4.57 564.2 197

578.6 4.69 578.2 198

581.9 5.11 580.1 199

590.6 4.76 590.2 200

595.9 4.96 594.1 201

377.4 2.84 377.2 202

383.5 3.21 383.2 203

385.5 3.51 385.2 204

391.5 2.97 391.2 205

391.5 3.05 391.2 206

399.5 3.68 399.3 207

413.5 3.20 413.2 208

419.5 3.74 419.2 209

421.5 3.97 421.0 210

425.5 4.13 425.2 211

425.5 4.13 425.2 212

427.5 4.37 427.2 213

432.5 3.04 432.2 214

433.5 3.94 433.2 215

441.6 4.52 441.3 216

447.5 4.03 447.2 217

477.6 4.66 477.2 218

485.6 4.75 485.3 219

489.6 4.67 489.2 220

499.6 4.89 499.3 221

505.6 4.43 505.2 222

507.5 4.27 507.2 223

511.6 4.63 511.2 224

539.6 4.68 539.2 225

539.6 4.84 539.2 226

541.6 4.69 541.2 227

314.4 3.02 314.2 228

328.4 3.27 328.2 229

340.4 3.32 340.2 230

362.4 3.41 362.2 231

368.5 3.87 368.2 232

370.5 4.15 370.2 233

376.5 3.65 376.2 234

376.5 3.52 376.2 235

382.5 4.16 382.2 236

384.5 3.45 384.2 237

390.5 3.70 390.2 238

390.5 3.79 390.2 239

390.5 3.06 390.2 240

396.9 3.74 396.1 241

400.4 3.50 400.2 242

404.5 4.19 404.2 243

410.5 4.60 410.2 244

418.5 4.26 418.2 245

418.5 4.36 418.2 246

420.5 3.52 420.2 247

428.5 4.59 428.2 248

430.4 3.87 430.2 249

432.5 4.40 432.2 250

438.9 4.43 438.1 251

440.5 4.60 440.2 252

440.5 3.96 440.2 253

462.5 4.59 462.2 254

462.6 4.24 462.2 255

463.5 3.39 463.2 256

468.6 4.99 468.2 257

472.5 4.50 472.2 258

476.5 4.65 476.2 259

476.5 4.74 476.2 260

490.6 4.78 490.2 261

490.6 4.84 490.2 262

490.6 4.23 490.2 263

492.5 4.59 492.2 264

496.6 5.04 496.2 265

510.6 5.09 510.2 266

520.6 4.63 520.2 267

524.6 5.20 524.2 268

524.6 4.75 524.2 269

530.5 4.85 530.2 270

564.6 5.24 564.2

1. Compounds of the general formula (I)

in which R¹ represents nitro, amino, acetamido or represents a group ofthe formula —NH—CO—CO—A or —NH—CH₂—CO—A, in which A represents hydroxylor (C₁-C₄)-alkoxy, R² and R³ are identical or different and denotehalogen, C₁-C₄-alkyl or trifluoromethyl, R⁴ represents a group of theformula

 in which E represents straight-chain or branched (C₁-C₄)-alkyl, R⁶ andR⁷ are identical or different and, independently of one another,represent straight-chain or branched (C₁-C₁₀)-alkyl which can besubstituted one or more times, identically or differently, by(C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, amino, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₄)-alkoxycarbonylamino, aminocarbonyl,(C₁-C₆)-alkoxycarbonyl, or by (C₆-C₁₀)-aryl or 5 to 6-membered saturatedor aromatic heterocyclyl with up to three heteroatoms from the series N,O and/or S, where aryl and heterocyclyl in turn are optionallysubstituted one or more times, identically or differently, by(C₁-C₄)-alkyl, aminocarbonyl, (C₁-C₄)-alkanoylamino or halogen, represent (C₆-C₁₀)-aryl or (C₃-C₈)-cycloalkyl, each of which can besubstituted by (C₁-C₄)-alkoxy, or  represent a 4- to 8-memberedsaturated heterocycle with up to two heteroatoms from the series N, Oand/or S, which can be substituted one or more times, identically ordifferently, by (C₁-C₄)-alkoxycarbonyl, oxo or (C₁-C₄)-alkyl, or R⁶ andR⁷ form, together with the nitrogen atom to which they are bonded, a 4-to 7-membered saturated heterocycle which optionally contains up to twoother heteroatoms from the series N, O and/or S, R⁸ representsstraight-chain or branched (C₁-C₁₀)-alkyl which can be substituted by(C₃-C₈)-cycloalkyl, phenyl or phenoxy, or represents (C₃-C₈)-cycloalkyl,(C₆-C₁₀)-aryl, biphenylyl or (C₁-C₆)-alkoxy, R⁹ representsstraight-chain or branched (C₁-C₈)-alkyl whose carbon chain can beinterrupted by —O— and which can be substituted by (C₃-C₈)-cycloalkyl orphenyl, or represents (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkenyl, phenyl orpyridyl,  where the aromatic ring systems mentioned both in R⁸ and in R⁹can, in each case independently of one another, in turn be substitutedby trifluoromethyl, halogen, (C₁-C₄)-alkoxy, (C₁-C₄)-alkyl or amino, orR⁸ and R⁹ form, together with the nitrogen atom and the carbonyl groupto which they are bonded, a 4- to 7-membered saturated heterocycle whichoptionally contains up to two other heteroatoms from the series N, Oand/or S, R¹⁰ represents straight-chain or branched (C₁-C₁₅)-alkyl whichcan be substituted by (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy, phenyl,phenoxy or benzyloxy, where the said aromatic radicals can in turn eachbe substituted up to three times, identically or differently, byhalogen, (C₁-C₆)-alkyl or (C₁-C₄)-alkoxy,  represents (C₃-C₈)-cycloalkylwhich can be substituted by (C₁-C₄)-alkoxy or phenyl,  represents(C₆-C₁₀)-aryl which can be substituted up to three times, identically ordifferently, by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halogen, cyano, amino,trifluoromethyl or phenyl, or  represents a 5- to 6-membered saturatedor aromatic, optionally benzo-fused heterocycle with up to twoheteroatoms from the series N, O and/or S, or  denotes a group of theformula —OR¹³ or NR¹⁴R¹⁵, in which R¹³ represents straight-chain orbranched (C₁-C₆)-alkyl, and R¹⁴ and R¹⁵ are identical or different and,independently of one another,  represent hydrogen, straight-chain orbranched (C₁-C₁₂)-alkyl, which can be substituted by aminocarbonyl, agroup of the formula —NR¹⁶R¹⁷, 5- to 6-membered heteroaryl whichcontains up to 3 heteroatoms selected from the series N, O and/or S orcan be substituted by phenyl, where phenyl is optionally substituted upto twice, identically or differently, by halogen, (C₁-C₄)-alkyl,trifluoromethyl or (C₁-C₄)-alkoxy,  represent (C₃-C₈)-cycloalkyl whichcan be substituted by (C₁-C₄)-alkyl,  represent (C₆-C₁₀)-aryl which canbe substituted up to three times, identically or differently, byhalogen, (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy, amino, phenylor phenoxy, or  represent a 5- to 7-membered, saturated or unsaturatedheterocycle which contains one or two nitrogen atoms and which can bebonded via a carbon or nitrogen atom and is optionally substituted by(C₁-C₄)-alkyl or an oxo group, where R¹⁶ and R¹⁷ are identical ordifferent and, independently of one another, represent hydrogen,(C₁-C₆)-alkyl, phenyl or (C₆-C₁₀)-arylsulphonyl, or  form, together withthe nitrogen atom to which they are bonded, a 3- to 7-membered saturatedheterocycle which optionally contains up to two other heteroatoms fromthe series N, O and/or S, or R¹⁴ and R¹⁵ form, together with thenitrogen atom to which they are bonded, a 4- to 7-membered saturatedheterocycle which can contain up to two other heteroatoms from theseries N, O and/or S and be substituted by amino, (C₁-C₆)-alkyl,(C₁-C₄)-alkanoyl, aminocarbonyl, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkoxycarbonylamino, phenyl or pyridyl, R¹¹ and R¹² areidentical or different and, independently of one another,  representhydrogen, straight-chain or branched (C₁-C₆)-alkyl, which can besubstituted one or more times, identically or differently, bymono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, (C₁-C₄)-alkoxy,(C₁-C₆)-alkoxycarbonyl, carboxyl, pyridyl or (C₆-C₁₀)-aryl, where thelatter in turn is optionally substituted by halogen, trifluoromethyl,(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy,  represent (C₃-C₈)-cycloalkyl orrepresent a 5- to 7-membered heterocycle which contains one to twonitrogen atoms and which can be bonded via a carbon or nitrogen atom,where cycloalkyl and heterocycle are optionally substituted by(C₁-C₄)-alkyl, or R¹¹ and R¹² form, together with the nitrogen atom towhich they are bonded, a 5- to 7-membered saturated, optionallybenzo-fused heterocycle which can contain up to two other heteroatomsfrom the series N, O and/or S and be substituted by amino,(C₁-C₆)-alkyl, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkoxy-carbonylamino orphenyl, and R⁵ denotes hydrogen, (C₁-C₄)-alkyl or (C₁-C₄)-alkanoyl, andthe respective salts and hydrates thereof show a pharmacological effectand can be used as pharmaceuticals or for producing pharmaceuticalformulations.
 2. Compounds of the general formula (I) according to claim1, in which E represents straight-chain or branched (C₁-C₄)-alkyl, R¹represents acetamido or represents a group of the formula —NH—CO—CO—A or—NH—CH₂—CO—A, in which A represents hydroxyl or (C₁-C₄)-alkoxy, R² andR³ are identical or different and denote halogen, methyl ortrifluoromethyl, R⁴ represents a group of the formula

 in which R⁶ and R⁷ are identical or different and, independently of oneanother,  represent straight-chain or branched (C₁-C₁₀)-alkyl which canbe substituted one or more times, identically or differently, by(C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy, 5- to 6-membered saturated oraromatic heterocyclyl with up to three heteroatoms from the series N, Oand/or S, or by (C₆-C₁₀)-aryl which in turn is optionally substitutedone or more times, identically or differently, by aminocarbonyl,(C₁-C₄)-alkanoylamino or halogen,  represent (C₃-C₈)-cycloalkyl whichcan be substituted by (C₁-C₄)-alkoxy, or  represent a 4- to 8-memberedsaturated heterocycle with up to two heteroatoms from the series N, Oand/or S which can be substituted one or more times, identically ordifferently, by (C₁-C₄)-alkyl, R⁸ represents straight-chain or branched(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₃-C₆)-cycloalkylmethyl or phenyl,R⁹ represents straight-chain or branched (C₁-C₈)-alkyl whose carbonchain can be interrupted by —O— and which can be substituted by phenyl,or (C₃-C₈)-cycloalkyl or phenyl which can be substituted by halogen,trifluoromethyl or (C₁-C₄)-alkyl, R¹⁰ represents straight-chain orbranched (C₁-C₁₀)-alkyl which can be substituted by (C₃-C₈)-cycloalkyl,(C₁-C₄)-alkoxy, phenyl or phenoxy, where the said aromatic radicals canin turn each be substituted up to three times, identically ordifferently, by halogen, (C₁-C₃)-alkyl or (C₁-C₄)-alkoxy,  represents(C₃-C₈)-cycloalkyl or represents phenyl which can be substituted up tothree times, identically or differently, by (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, halogen or phenyl, or  represents a 5- to 6-memberedsaturated or aromatic, optionally benzo-fused heterocycle with up to twoheteroatoms from the series N, O and/or S, or  denotes a group of theformula —OR¹³ or —NR¹⁴R¹⁵, in which R¹³ represents straight-chain orbranched (C₁-C₆)-alkyl, and R¹⁴ and R¹⁵ are identical or different and,independently of one another,  represent hydrogen or straight-chain orbranched (C₁-C₆)-alkyl which can be substituted by phenyl which in turnis optionally substituted up to twice, identically or differently, byhalogen, (C₁-C₄)-alkyl, trifluoromethyl or (C₁-C₄)-alkoxy,  represent(C₃-C₈)-cycloalkyl which can be substituted by (C₁-C₄)-alkyl, or represent phenyl, naphthyl or biphenylyl, R¹¹ and R¹² are identical ordifferent and, independently of one another,  represent hydrogen orstraight-chain or branched (C₁-C₆)-alkyl which can be substituted byphenyl which in turn is optionally substituted by halogen,trifluoromethyl, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy, or  represent(C₃-C₈)-cycloalkyl which can be substituted by (C₁-C₄)-alkyl, and R⁵denotes hydrogen or (C₁-C₄)-alkanoyl, and the respective salts andhydrates thereof.
 3. Compounds of the general formula (I) according toclaim 1, in which E represents straight-chain or branched (C₁-C₄)-alkyl,R¹ represents a group of the formula —NH—CO—COOH or —NH—CH₂—COOH, R² andR³ are identical or different and denote chlorine, bromine, methyl ortrifluoromethyl, R⁴ represents a group of the formula

 in which R⁶ and R⁷ are identical or different and, independently of oneanother,  represent a straight-chain or branched (C₁-C₈)-alkyl which canbe substituted by (C₅-C₈)-cycloalkyl, pyridyl, furyl, tetrahydrofuryl orone to three times by methoxy or ethoxy, or which is substituted byphenyl which in turn is optionally substituted once to twice,identically or differently, by fluorine, chlorine, aminocarbonyl oracetamido,  represent (C₃-C₈)-cycloalkyl which can be substituted bymethoxy or ethoxy, or  represent pyrrolidinyl or piperidinyl, each ofwhich can be substituted one or more times by methyl, R⁸ representsstraight-chain (C₁-C₇)-alkyl, (C₃-C₆)-cycloalkylmethyl,(C₃-C₆)-cycloalkyl or phenyl, R⁹ denotes straight-chain or branched(C₁-C₄)-alkyl which can be substituted by phenyl, or (C₃-C₆)-cycloalkylor phenyl which can be substituted by chlorine or fluorine, R¹⁰represents straight-chain or branched (C₁-C₄)-alkyl which can besubstituted by (C₃-C₆)-cycloalkyl, phenyl or phenoxy, where the saidaromatic radicals can in turn each be substituted up to three times,identically or differently, by fluorine, chlorine or (C₁-C₃)-alkyl, or represents biphenylyl, 2,3-dihydro-1-benzofuranyl,3,4-dihydro-2H-1-benzopyranyl or 3,4-dihydro-1H-2-benzopyranyl, or represents a group of the formula —NR¹⁴R¹⁵, in which R¹⁴ denoteshydrogen or straight-chain or branched (C₁-C₃)-alkyl, and R¹⁵ representsstraight-chain or branched (C₁-C₄)-alkyl which can be substituted byphenyl which in turn is optionally substituted by methyl, methoxy,trifluoromethyl, fluorine or chlorine, or represents naphthyl,biphenylyl or (C₃-C₆)-cycloalkyl, R¹¹ denotes hydrogen or straight-chainor branched (C₁-C₃)-alkyl, and R¹² represents straight-chain or branched(C₁-C₄)-alkyl which can be substituted by phenyl which in turn isoptionally substituted by methyl, methoxy, trifluoromethyl, fluorine orchlorine, or  represents cyclopentyl or cyclohexyl, each of which can besubstituted by (C₁-C₃)-alkyl, and R⁵ denotes hydrogen or (C₁-C₄)-alkyl,and the respective salts and hydrates thereof.
 4. Compounds of thegeneral formula (I) according to claim 1, in which R¹ represents a groupof the formula —NH—CO—COOH or —NH—CH₂—COOH, R² and R³ are identical ordifferent and denote chlorine, bromine, methyl or trifluoromethyl, R⁴represents a group of the formula

 in which R⁶ and R⁷ are identical or different and, independently of oneanother,  represent straight-chain or branched (C₁-C₈)-alkyl which canbe substituted by phenyl which in turn is optionally substituted once totwice, identically or differently, by fluorine, chlorine, aminocarbonylor acetamido, or can be substituted by (C₅-C₈)-cycloalkyl, pyridyl,furyl, tetrahydrofuryl or once to three times by methoxy or ethoxy, represent (C₅-C₈)-cycloalkyl which can be substituted by methoxy orethoxy, or  represent pyrrolidinyl or piperidinyl, each of which can besubstituted one or more times by methyl, and R¹⁰ representsstraight-chain or branched (C₁-C₄)-alkyl which can be substituted by(C₃-C₆)-cycloalkyl, phenyl or phenoxy, where the said aromatic radicalscan in turn each be substituted up to three times, identically ordifferently, by fluorine, chlorine or (C₁-C₃)-alkyl, or  representsbiphenylyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-2H-1-benzopyranyl or3,4-dihydro-1H-2-benzopyranyl, and R⁵ denotes hydrogen, and therespective salts and hydrates thereof.
 5. Process for preparingcompounds of the general formula (I) according to claim 1, characterizedin that (A) compounds of the formula (II)

in which PG² denotes a hydroxyl protective group or a resin suitable forsolid-phase synthesis, and R⁴ has the meaning indicated in claim 1, arereacted in the presence of a base with compounds of the general formula(III)

in which R² and R³ have the meaning indicated in claim 1, and R^(1′)represents a suitable group from the scope of meanings of R¹, preferablyrepresents the NO₂ group, and Hal represents chlorine or fluorine, togive compounds of the formula (IV)

in which R^(1′), R², R³, R⁴ and PG² have the meaning indicated above, or(B) compounds of the formula (V)

in which PG² has the meaning indicated above, and R represents asuitable precursor of the R⁴ group, preferably represents CHO,(C₁-C₆)-alkoxycarbonyl or nitro, are reacted in the presence of a basewith a compound of the formula (III)

in which R^(1′), R², Hal and R³ have the meaning indicated above, togive a compound of the formula (VI)

in which R, R^(1′), R², R³ and PG² have the meaning given above, and thelatter is converted into compounds of the formula (IV) by converting thesubstituent R in a suitable manner to the substituent R⁴, and in thatfinally the protective group PG² is eliminated from the compound of theformula (TV) and, where appropriate, the substituents are modified orderivatized in a suitable way by standard reactions.
 6. Pharmaceuticalcontaining at least one compound of the general formula (I) according toclaim
 1. 7. Process for producing pharmaceuticals, characterized in thatat least one compound of the general formula (I) according to claim 1 isconverted with excipients and/or carriers into a suitable administrationform.
 8. Use of compounds of the general formula (I) according to claim1 for producing pharmaceuticals.
 9. Use according to claim 8 forproducing pharmaceuticals for the treatment and/or prophylaxis ofarteriosclerosis and/or hypercholesterolaemia.
 10. Use according toclaim 8 for producing pharmaceuticals for the prophylaxis and/ortreatment of pathological states which can be treated with naturalthyroid hormone.